Mitochondrial DNA (mtDNA) base substitution mutations are believed too be a common cause of age-related degenerative diseases as well as cancer. However, no mouse model has been generated in which a mtDNA base substitution has been stably introduced into the mouse germline and resulted in an inherited predisposition to and age-related disease or cancer. We now report the introduction of a mtDNA harboring a missense mutation in the COI gene into the mouse that predisposes the mice to develop myopathy and hypertrophic cardiomyopathy as well as certain hyperproliferative conditions in an age-related manner.
United States Patent Application Publication No. 2007/0022488 (Prolla et al.) entitled “Mouse Model for Aging” describes a mouse model for mammalian aging comprising a transgenic mouse having a genomic mtDNA mutation. In one embodiment, this mouse model comprises a mouse having a genomic mutation in the exonuclease domain II (ExoII) of a mitochondrial DNA polymerase gamma (POIG) gene, wherein the mutation leads to high levels of mutations in polymerase mtDNA. The entire disclosure of United States Patent Application Publication No. 2007/0022488 (Prolla et al.) is hereby expressly incorporated herein by reference.
As early as 2005, Applicants had shown that base substitution mutations in the human mtDNA can result in age-related myopathy, cardiomyopathy, and neuropathy (Wallace D. C., 2005. Annual Rev Genet 39:359-407) and that missense mutations in the mtDNA COI gene are associated with increased risk for prostate cancer (Petros, J. A., et al., 2005. Proc. Natl. Acad. Sci. 102: 719-724).
Three publications are known to have previously reported the introduction of mtDNA variants into the mouse germline. In the first report, which was from Applicant's laboratory, a base substitution in the mtDNA 16S rRNA was introduced into the moue germline. However, this mutation proved to be too severe and all of the mutant mice died before they could reproduce and transmit the mutation to subsequent generations Sligh, J. E., et al, 2000, Proc. Natl. Acad. Sci. USA 97:14461-14466. The second paper reported the introduction of a heteroplasmic (mixed mutant and wild type) mtDNA deletion mutation into the mouse germline. While the mutant mtDNA was transmitted through the female germline in the heteroplasmic state, the deleted mtDNA also segregates. Hence, this mutation was not stable and the phenotype was not consistent. Inoue, K. et al., 2000, Nature Genetics 26: 176. The third paper reported the introduction of the same COI mutation into the mouse germline that we declare here. However, these authors declared that the mice had no phenotype, probably because they did not understand that mitochondrial pathologies generally have a delayed onset and progressive course. Kasahara A et al, 2006, Hum Molec Genet 15:871.
There remains a need in the art for the development of additional devices and methods for controlling the depth or positioning of needles, cannulae and other diagnostic/therapeutic devices within the walls of organs or other tissue masses.